There is increasing evidence that abnormal cortical connectivity may be an important factor in the pathophysiology of schizophrenia. Supporting data has come from studies of schizophrenia, including findings of reduced correlations between volumes of frontal and temporal gray matter regions, of altered activation patterns from PET studies, and indications of aberrant cell migration. While white matter provides the physical foundation for corticocortical and subcortico-cortical connectivity, there has been little in vivo study of white matter, perhaps because of a lack of appropriate tools. Diffusion Tensor Imaging (DTI) is a new magnetic resonance imaging (MRI) method which is uniquely suited to the study of white matter since it can be used to quantify the magnitude and directionality of tissue water mobility (i.e., self-diffusion) in three dimensions. Structures in white matter (WM) such as myelin sheaths, membranes, and white matter tracts can act as barriers to water mobility, causing the water molecules to move farther along paths that are parallel to fibers rather than those that are perpendicular to these fibers. When there is a directional dependence of water mobility, the diffusion is described as being anisotropic. This anisotropy can be quantified and used to assess the micro-structural organization of white matter fibers. Highly regular, organized fibers will have high anisotropy; less well organized fibers will have lower anisotropy measures. In a preliminary study of 10 chronic schizophrenic subjects (SZ) and 10 normal controls (NC), we used DTI to assess white matter anisotropy. The WM fractional anisotropy (FA) was found to be significantly reduced in the schizophrenic subjects which was interpreted as evidence of compromised white matter connectivity. Our preliminary study was among the first in vivo reports of WM microstructure abnormality in schizophrenia. This finding is important in that it uncovered an aspect of brain structure and physiology that had not yet been considered important to the pathophysiology of schizophrenia. Further in vivo studies are now needed to confirm this initial finding and to determine its relationship to clinical expression of the disease. The specific aims of this proposal are to: 1) confirm our initial finding of decreased white matter fractional anisotropy (FA) with a new group of schizophrenic patients and normal controls, 2) Examine the functional correlates of abnormal FA in schizophrenia.